Heart rate is a major determinant of oxygen consumption in patients with ischaemic heart disease. Its pharmacological modulation is increasingly the focus of therapeutic approaches to alleviate symptoms and prolong survival. It is the simplest cardiovascular variable to measure accurately and reproducibly. Many long-term follow-up studies suggest that elevated heart rate increases all-cause mortality, cardiovascular disease and sudden death in patients with known or suspected coronary heart disease, survivors of myocardial infarction and patients with hypertension. These links hold for men and women, and are unrelated to ethnic origin. The effect on sudden death or total mortality increases as a function of heart rate such that an increase in heart rate by more than 40 beats/min doubles total mortality. Conversely, low heart rate reduces risk for coronary artery disease and sudden death. Primary and secondary prevention studies in myocardial infarction indicated that elevated heart rate in susceptible patients predicts risk for developing myocardial infarction and death. Prophylactic beta-blockers attenuate risks for reinfarction, sudden death and total mortality; these effects correlate with reduced heart rate, thus providing a compelling basis for developing agents that reduce heart rate exclusively as antianginal agents for the therapy of myocardial ischaemia with broader therapeutic implications.
Heart rate as a predictor of risk for
epidemiological observations The integral relationship between resting heart rate, coronary artery disease and mortality has been documented in a number of epidemiological studies. These studies include, but are not
confined to, the Framingham Heart Study,7,9 the first National Health and Nutrition Examination Survey (NHANES 1),10 the NHANES 1 Epidemiological Follow-up Study (NNHEFS),11 the Chicago Employee Studies6 and the Göteborg Primary Prevention Trial.14 The Chicago Employee study is mentioned in passing because it is one of the
oldest in the series, and its directional data are, in general, consistent with the results of the subsequent studies. In the discussion that follows, only aspects of the findings in those studies that address the impact of increased heart rate relative to mortality and morbidity are mentioned.
Heart rate and cardiovascular mortality
The longest follow-up was reported from the Framingham Heart Study — a prospective study that was started in 1948.9 The report on the relationship between heart rate and cardiovascular mortality focused on 5070 individuals who were free of cardiac disease at entry into the study. They were subjected to biennial examinations of a wide range of variables, including the following: cardiovascular examination and history; an ECG; measurement of vital capacity, body weight and skin-fold thickness; various blood chemistry and blood pressure determinations; and history of smoking. The resting ECG was used for the determination of heart rate. Over the followup period of 30 years there were 1876 total deaths, of which 894 were cardiovascular in origin. For both sexes, all-cause, cardiovascular and coronary disease mortality increased progressively relative to the antecedent resting heart rates
determined biennially. There was no suggestion of critical values or thresholds that could be labelled as safe or hazardous. The trend significance was at P < 0.01, as it was for sudden death (Table 1). The effect of heart rate on mortality or sudden death was independent of associated cardiovascular risk factors, and death rate was higher in man than in women. The relationship between heart rate, coronary artery disease and death was also investigated systematically in NHEFS.11 The participants in that study were screened from those who were 25— 74 years old at the time of the initial survey, which was conducted during the period 1971— 1975. From the initial 7594 patients at baseline, 5136 white and 859 black people (age range 45— 74 years) remained for analysis after all defined exclusion criteria were met and follow-up variables established. The duration of follow-up for this analysis was 6—13 years, with an average of 9.9 years for white subjects and 10.3 years for the black survivors. It is noteworthy that, in
contrast to the Framingham Study, heart rates were not quantified by ECG but were obtained by a physician who counted the radial pulse for 30 s. The relative risk for the incidence of coronary heart disease (CHD) was significantly elevated in white men with pulse rate greater than 84 beats/min as compared with those with rates under 74 beats/min, after correcting for multiple risk factors. The incidence of CHD was also increased in white women with elevated pulse rate. The risks for death from all causes, cardiovascular diseases and non-cardiovascular diseases were also elevated for white men with raised pulse rate, and these findings was independent of other factors. It should be emphasized that risks for death and cardiovascular diseases were also increased in the case of black
men and women with elevated pulse rate, but the association with cardiovascular diseases and high pulse rate was particularly striking in the case of black women, even after adjustment for all of the baseline risk factors. Similar data on the incidence of all-cause mortality as well as CHD mortality were reported in the Göteborg Primary Prevention Trial,conducted in Sweden.14 In that study, 7455 patients were enrolled and followed as a function of heart rate at entry for a mean of 11.8 years. Deaths were stratified into total mortality, and death due to coronary artery disease, cancer and stroke, and other deaths. The follow-up data are presented in Fig. 1. It is noteworthy that the rate
of death from all causes and from cardiovascular disease increased as a function of increasing heart rate or when pulse rate increased beyond 84 beats/min, as was reported in NNHEFS.11 Finally, heart rate as a prognostic factor for CHD and mortality was also determined in three distinct epidemiological studies conducted 20 years ago.6
The associations between heart rate and death from cardiovascular diseases, coronary artery disease and sudden cardiac death from CHD, as well as mortality from all causes, were studied prospectively in middle-aged white male
employees: 1233 men aged 40—59 years from the Chicago Peoples Gas Company followed for 15 years; 1899 men aged 40—55 years from the Chicago Western Electric Company followed for 17 years; and 5784 men aged 45—64 years of age from the Chicago Heart Association Detection Project in Industry followed for 5 years. Despite the
relatively short period of follow-up, in a univariate analysis mortality from cardiovascular or noncardiovascular
causes increased with increasing heart rate. In a multivariate Cox regression analysis, controlling for hypertension, age, serum cholesterol, number of cigarettes smoked per day and relative weight, heart rate emerged as a significant risk factor for sudden death in two of the three studies. In sum, the authors concluded that the results of the three studies suggested that high heart rate may be an independent risk factor for sudden death from CHD.
Risk for high heart rate in hypertension
and in the elderly
It has been shown that hypertensive patients generally have a higher heart rate than do comparable normotensive persons.10 Gillman et al.12 followed 4530 hypertensive persons (blood pressure ≥140 mmHg systolic and ≥90 mmHg diastolic; age range 35—74 years) from the Framingham Heart Study for 36 years; those investigators found that, for the individuals who had increases in heart rates exceeding 40 beats/min, the total mortality more than doubled over this period. The details are summarized in Fig. 2. The rapid heart rate that the individuals had was not related to pre-existing illness but appeared to be an independent risk factor for cardiovascular death in those with
hypertension. Thus, the heart rate data relative to the impact on mortality are consistent with those reported for patients with known CHD9,11 and those for patients who had sustained but survived myocardial infarction, as discussed below.15 The data suggest that treatment regimens for hypertension may need to include heart rate
lowering drugs. Of interest also is the outcome of the study reported by Aronow et al.,26 who evaluated the
risk for high heart rate in elderly patients (60— 100 years, mean age 81 years) who had hypertensive or other forms of heart disease and were in sinus rhythm. That study was prospective and conducted in 1311 patients in whom mean
heart rates were quantified from 24-h Holter recordings. The data indicated that male sex, increasing age and mean 24-h heart rates were independent risk factors for new coronary events.